The objective of this research is to define the role for PFC-dependent inhibitory control in processes that likely contribute to addiction. We have shown that repeated exposure to cocaine (COC), PCP or THC, causes aberrant cognitive-motivational function and neurobiological alterations in cortico-limbic-striatal circuits in rodents and monkeys. Short-term COC exposure was sufficient to produce persistent and selective deficits in reversal learning and inhibition of pre-potent responding, effects indicative of selective OFC dysfunction, but did not alter extinction learning, attentional selection or working memory. Diminished inhibitory control was associated with increases in the motivational significance of reward-related stimuli. These drug-induced impairments were linked to, and can be mimicked by, altered cAMP-regulated intracellular signaling within the PFC and limbic-striatal regions in rodents suggesting that such adaptations may underlie alterations in inhibitory control. Proteomics analysis of synaptoneurosomes after prior chronic COC exposure to monkeys identified alterations in proteins involved in synaptic function and activity-dependent plasticity, with distinct cortico-striatal patterns. A large number of regulated proteins were associated with cAMP-regulated signaling networks, cytoskeletal, cell adhesion, vesicle trafficking and metabolic functions. Together, these data support our hypothesis of frontal-striatal dysfunction in addiction yet the causal relationship between PFC dysfunction and addiction remains to be determined. Here we will investigate the interaction between COC- induced and pre-existing individual differences in OFC-mediated inhibitory control function on the development of addictive-like behaviors in established animal models. Aim I will determine the link between OFC-dependent inhibitory control function and compulsive drug-seeking behavior. Separate groups of rats will be examined on either cue-motivated COC-seeking measured by responding on a second-order schedule of COC self-administration or COC-seeking behavior in conflict with intermittent presentation of aversive stimuli. Another goal is to determine the neurobiological mechanisms of these interactions using biochemical analyses. Aim II will test the contribution of selected drug-induced neurobiological alterations in the OFC focusing on cAMP-regulated signaling and the transcription factor Sp1 that was identified in our proteomic analyses. Sp1 controls D2 receptor expression and has not previously been implicated in stimulant addiction. Aim III will extend these data by confirming in monkeys the interaction between individual and COC-induced differences in OFC function on inhibitory control, incentive motivation, and response conflict, and the associated neurobiological alterations using state-of-the-art proteomic techniques. Viral-mediated gene transfer will be used to manipulate Sp1 in the OFC of rats (Aim II) or monkeys (Aim III) to determine its effects on OFC-dependent inhibitory control and potential role in compulsive aspects of behavior. Together these studies should significantly advance our understanding of OFC-inhibitory control and vulnerability to addiction. PUBLIC HEALTH RELEVANCE: We have shown that prior repeated exposure to addictive drugs such as cocaine produces persistent deficits in response inhibition and incentive motivational function that are associated with neurobiological alterations in cAMP/PKA-regulated signaling in cortico-limbic-striatal brain regions in rodents and monkeys. Such changes may be directly relevant to understanding addiction as an inability to modulate changes in reward-motivated behaviors may increase the motivational significance of reward-associated cues and contribute to relapse and difficulties in inhibiting drug-associated thoughts and behaviors. We hypothesize the level of orbitofrontal cortical function prior to cocaine exposures may also predict the extent of cocaine-induced dysfunction, and we will investigate how cocaine-induced and individual differences in orbitofrontal-mediated processes can interact to affect the development of cognitive dysfunction and addictive-like behavior.